Vendredi 29 septembre de 11h00 à 12h00
Salle des séminaires IBS
Par Dr Thomas H. Sharp (Department of cell & chemical biology, Leiden University Medical Center, Netherland)
Hôte : Christine Gaboriaud (IBS/Groupe Complement, anticorps et maladies infectieuses)
In the classical pathway of complement activation, antigen-antibody immune complexes bind complement component C1, through its multimeric C1q recognition module, and activate the associated proteases C1r and C1s. This process initiates the proteolytic complement cascade that leads to clearance of the targeted cells. Complement can also be activated by pentraxins, proteins of the innate immune system that act as functional homologues of antibodies. However, how antibodies and pentraxins bind and activate C1 remains unclear. We apply multimodal imaging techniques to investigate the molecular steps in complement activation, through binding of pentraxins and antibodies and formation of oligomeric activatory platforms, and how C1 binds to these platforms. I will discuss how we use 3D cryo-electron tomography and structural biology, combined with AI-based structure prediction, to solve the structures of various complement components. Our recent work includes visualizing IgG3 antibodies for the first time, which revealed a unique oligomeric morphology, as well as how long and short pentraxins bind and activate complement. These structures reveal insights into various activation mechanisms. With this new structural knowledge, we are now developing DNA nanotechnology to control immune system activation and explore a novel immunotherapeutic route. I will then focus on how we are developing correlative cryo-fluorescence and cryo-super-resolution techniques, which we will use to study how immune complexes interact with cells and tissues by applying in situ structural biology.